JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Ming Su,Lei Ye,Yunbing Tang,Shaowei Wang,Zhiyan Hu,Huitao Li,Yiyan Wang,Xiaoheng Li,Yi Liu,Ren-Shan Ge
Resveratrol and its analogs are phytochemicals. Human 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1) synthesizes steroid hormones for normal pregnancy or promoting cancer metastasis. Whether they inhibit 3β-HSD1 remains unclear. In this study, the inhibitory potency, mode of action, structure–activity relationship, and docking parameters of resveratrol and its analogs on 3β-HSD1 and rat homolog 3β-HSD4 were analyzed. The inhibitory potency of these chemicals on human 3β-HSD1 was 4,4′-dihydroxystilbene (IC50, 3.68 μM) > pinostilbene (8.07 μM) > pinosylvin (10.60 μM) > lunularin (26.84 μM) > resveratrol (30.20 μM) > dihydroresveratrol (>100 μM) = oxyresveratrol (>100 μM) > dihydropinosylvin (ineffective at 100 μM). Resveratrol analogs and metabolites are mixed or competitive inhibitors of human 3β-HSD1. Resveratrol and 4,4′-dihydroxystilbene inhibited progesterone secretion by human JAr cells at ≥1 μM. Resveratrol (IC50, 32.09 μM) and pinosylvin (34.71 μM) significantly inhibited rat placental 3β-HSD4 activity. Docking analysis shows that resveratrol analogs and metabolites bind the steroid-binding sites of human 3β-HSD1 and rat 3β-HSD4 and interact with the catalytic residues Ser125/Thr125 and Tyr155. The negative correlation of LogP and IC50 values for human 3β-HSD1 indicates that lipophilicity of chemicals plays a critical role in the inhibitory effect of chemicals. In conclusion, 4,4′-dihydroxystilbene, pinostilbene, and pinosylvin effectively inhibit human 3β-HSD1 depending on their lipophilicity, thereby acting as potential therapeutic agents.
研究领域:
生物化学
·
药理学
·
分子生物学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·Vol. 74
·期 32
·25059-25074
·
IF 6.7
Che Huiyi,Ren Xiya,Wang Shaowei,Wang Lingfei,Gong Chaochao,Shu Yu,Tang Yunbing,Zhang Pu,Ge Ren-Shan,Ying Yingfen
Environmental
exposure to herbicides has raised significant
concerns.
However, whether herbicides affect placental 3β-hydroxysteroid
dehydrogenase/Δ 5 -Δ 4 isomerase (3β-HSD)
remains unclear. This study investigated the inhibitory effects of
14 herbicides, especially dinitroanilines, on human (h3β-HSD1)
and rat (r3β-HSD4), key enzymes in progesterone biosynthesis.
In vitro assays showed isopropalin and oryzalin potently inhibited
h3β-HSD1 (IC 50 39.56 and 52.99 μM) via mixed-type
inhibition. Inplacental JAr cells, oryzalin and profluraline suppressed
progesterone synthesis at 100 μM, while isopropalin had no effect.
Species-dependent inhibition was observed; oryzalin was most potent
against r3β-HSD4 (IC 50 33.52 μM), and cyanazine
also inhibited the rat isoform. Molecular docking indicated their
binding to the NAD + -binding pocket. SAR and pharmacophore
modeling identified molecular volume and flexibility as key for h3β-HSD1
potency. Network toxicology linked herbicide exposure to recurrent
pregnancy loss via steroidogenic genes. These findings provide mechanistic
evidence that specific herbicides disrupt progesterone production
and may contribute to adverse reproductive outcomes.
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高影响因子
TOXICOLOGY LETTERS
·
2023
·
IF 3.5
Yingna Zhai,Shaowei Wang,Bingru Zhang,Yunbing Tang,Hong Wang,Jingjing Li,Zhiyan Hu,Yiyan Wang,Huitao Li,Ren-shan Ge
3β-Hydroxysteroid dehydrogenase/steroid Δ 5,4 -isomerase 1 (3β-HSD1) plays a critical role in the biosynthesis of progesterone from pregnenolone in the human placenta to maintain normal pregnancy. Whether they inhibit placental 3β-HSD1 and mode of inhibition remains unclear. In this study, we screened 21 pesticides and fungicides in five classes to inhibit human 3β-HSD1 and compared them to rat homolog 3β-HSD4. 3β-HSD activity was measured by catalyzing pregnenolone to progesterone in the presence of NAD + . Of the 21 chemicals, azoles (difenoconazole), thiocarbamates (thiram and ferbam) and organochlorine (hexachlorophene) significantly inhibited human 3β-HSD1 with half maximal inhibitory concentration (IC 50 ) values of 2.77, 0.24, 0.68, and 17.96 μM, respectively. We also found that difenoconazole, ferbam and hexachlorophene are mixed/competitive inhibitors of 3β-HSD1 while thiram is a mixed/noncompetitive inhibitor. Docking analysis showed that difenoconazole and hexachlorophene bound steroid-binding site. Difenoconazole and hexachlorophene except thiram and ferbam also significantly inhibited rat 3β-HSD4 activity with IC 50 of 1.12 and 2.28 µM, respectively. Thiram and ferbam significantly inhibited human 3β-HSD1 possibly by interfering with cysteine residues, while they had no effects on rat 3β-HSD4. In conclusion, some pesticides potently inhibit placental 3β-HSD, leading to the reduction of progesterone formation.
研究领域:
药理学
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毒理学
·
生殖生物学
·
酶学
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PubMed
高影响因子
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